Our objective is to understand the mechanism conferring protection from diabetes in autoantibody positive HLADQA1*0102, DQB1*0602 subjects. We will use a unique patient population in our studies. The Diabetes prevention Trial- type 1 (DPT-1) has screened more than 50,000 relatives for th presence of ICA+. Antibody positive subjects who carry the H.A. DQA1*0102, DQB1*0602 haplotype are excluded from further participation in the DPT-1 since their risk of disease is low. This screening process has now identified more then ninety ICA+ relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Thus, the identification of these autoantibody positive subjects through the DPT-1 provides a unique opportunity to understand how the presence of H.A. DQA1*0102, DQB1*0602 protects from clinical disease in subjects who are otherwise at risk for diabetes. This proposal will test two hypothesis in the subjects. We first propose that DQB1*0602 subjects are protected from beta cell destruction because of decreased spreading of the immune response. To test this hypothesis, we will determine whether ICA+ 0602 positive relatives have evidence of beta cell dysfunction, whether they have decreased spreading of the immune response to autoantigens, and whether these two aspects of the diabetes disease process are related. Our second hypothesis proposes that DQB1*0602 protection occurs because of an increased IL-4 response which regulates the cellular response to islet antigens. To test this hypothesis, we will examine the concentration of IL-4, the autoantibody isotypes and subtypes present, and the precursor frequency of autoreactive T cells in these subjects and determine the relationship between these measures of the immune response. This proposal includes collaborative agreements between the University of Washington and the Universities of Florida (Gainesville), South Florida (Tampa), and Colorado.